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International Journal of Surgery 9 (2011) 5e12

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International Journal of Surgery

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Advances in resuscitation strategies

Hasan B. Alam*
Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

a r t i c l e i n f o a b s t r a c t

Article history: Shock, regardless of etiology is characterized by decreased delivery of oxygen and nutrients to the tissues
Received 4 May 2010 and our interventions are directed towards reversing the cellular ischemia and preventing its conse-
Received in revised form quences. The treatment strategies that are most effective in achieving this goal obviously depend upon
30 July 2010
the different types of shock (hemorrhagic, septic, neurogenic and cardiogenic). This brief review focuses
Accepted 4 September 2010
Available online 15 September 2010
on the two leading etiologies of shock in the surgical patients: bleeding and sepsis, and addresses
a number of new developments that have profoundly altered the treatment paradigms. The emphasis
here is on new research that has dramatically altered our treatment strategies rather than the basic
pathophysiology of shock.
Resuscitation Ó 2010 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

1. Hemorrhagic shock of early soft thrombus, coagulopathy, and hemodilution.9e12 A

systematic review of 52 animal trials concluded that fluid resuscita-
Exsanguination is one of the leading causes of death following tion appeared to decrease the risk of death in models of severe
trauma1,2 and prompt hemorrhage control along with adequate hemorrhage (RR ¼ 0.48), but increased the risk of death in those with
fluid resuscitation are the key components of early trauma care. less severe hemorrhage (RR ¼ 1.86).13 Furthermore, hypotensive
Similarly, hemorrhage is often encountered in non-trauma patients resuscitation (targeting a lower blood pressure), whenever tested,
as a complication following major surgeries. Despite hemorrhage reduced the risk of death (RR ¼ 0.37). Similarly, a critical review of the
being a common problem, the optimal resuscitative strategy literature failed to find any evidence that pre-hospital advanced life
remains controversial, with vigorous ongoing debates about issues support and improved outcomes in trauma patients.14 In a study that
such as the type of fluid, volume, rate, route of administration, and has generated vigorous debate since its publication in 1994,15 hypo-
endpoints of resuscitation. tensive patients with penetrating torso injury were randomized to
routine fluid resuscitation, or resuscitation was delayed until bleeding
had been surgically controlled. The results of this study demonstrated
1.1. Futility of current methods/adverse effects of aggressive
a survival advantage in the delayed resuscitation group (70% vs. 62%,
p ¼ 0.04). Despite all the controversy, the most impressive finding
remains that withholding fluid resuscitation until hemorrhage
Although it is widely believed that early aggressive fluid resusci-
control did not increase the mortality. The issue of timing and volume
tation is beneficial, clinical and basic science literature fails to provide
of fluid resuscitation in bleeding patients has also been addressed by
conclusive supporting evidence.3e7 As a matter of fact, the basic
The Cochrane Database of Systematic Reviews.16 Only six randomized
rationale for administering intravenous fluids in patients with
clinical trials met the inclusion criteria, and a careful review failed to
ongoing bleeding has been challenged repeatedly for almost a
provide any evidence in support of (or against) early or large volume
century.8 Theoretically, fluid resuscitation in the absence of (or prior
intravenous fluid administration in uncontrolled hemorrhage. Based
to) hemorrhage control can exacerbate bleeding due to the disruption
upon all this information, it is reasonable to conclude that fluid
resuscitation is not a substitute for early hemorrhage control. Low
* Division of Trauma, Emergency Medicine and Surgical Critical
volume, careful resuscitation is reasonable, especially when trying to
165 Cambridge Street, Suite 810, Boston, MA 02114. Tel.: þ1 617 643 2433. get a dying patient to definitive care. However, early aggressive fluid
E-mail address: resuscitation, in the absence to hemorrhage control, can’t be justified.

1743-9191/$ e see front matter Ó 2010 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
6 H.B. Alam / International Journal of Surgery 9 (2011) 5e12

In addition to the impact of resuscitation on bleeding, resusci- products and vasopressors is replacing large volume crystalloid
tation fluids have profound cellular effects. It is now widely infusion. Prompted by the recommendations of some con-
recognized that resuscitation fluids are not completely innocuous, sensus conferences29e32 and due to the unique logistical
and they may actually potentate the cellular injury caused by challenges of the battlefield, the resuscitation strategies being
hemorrhagic shock.17 This concept of “resuscitation injury” has utilized by the US military have changed dramatically: resus-
steadily gained attention since a report by the Institute of Medicine citation is selective, emphasizing low volume and practical
(1999) described in detail the wide spectrum of adverse conse- endpoints, and the use of fluids with logistical advantages (e.g.
quences that can follow resuscitative efforts.18 Historically, the hetastarch) is preferred. The endpoint of resuscitation is not
concept of large volume crystalloids resuscitation was a product of a normal BP, but simply a palpable radial pulse and normal
seminal work by Shires, Moyer, Moss and others during the mental status (in the absence of head injury). Thus, IV fluids are
1960s19e22 and it became common practice during the Vietnam given only selectively, and in much less volumes. Also, early
conflict. Their work suggested that infusion of large volume hemorrhage control is prioritized over aggressive fluid resus-
isotonic crystalloids improved survival, and resuscitation fluids citation. It is difficult to determine the direct impact of these
were needed not only to replace the intra-vascular volume loss, but new strategies on combat casualty outcomes, but is very
also to replenish interstitial deficits. Therefore, these investigators encouraging to note that for the first time since the Crimean
recommended fluid replacement equal to three times the volume of War, the killed in action rate has markedly dropped below the
blood loss (and as high as 8:1 for severe shock). At that time the historic 20% to around 10e14%.33 Hypotensive resuscitation
emphasis was on restoration of intra-vascular and interstitial fluid can be performed by infusing fluids to achieve a desired goal
deficits, without much importance attached to the cytotoxic effects (e.g. target blood pressure), or at a pre-determined fixed rate.
of crystalloid fluids. Isotonic fluids were used widely in Vietnam Pre-clinical data shows that resuscitation to target mean arte-
and it was during this period that the appearance of “shock lung/Da rial pressure (MAP) of 40 mmHg, as opposed to 80 mmHg or
Nang lung” (later termed acute respiratory distress syndrome or higher not only results in decreased blood loss but also in better
ARDS) was first described in soldiers that received massive crys- splanchnic perfusion and tissue oxygenation,34 less acidemia,
talloid resuscitation. Today, ARDS and Multiple Organ Dysfunction hemodilution, thrombocytopenia, and coagulopathy,35 decr-
Syndrome are major causes of delayed mortality in trauma patients. eased apoptotic cell death and tissue injury35,36 and improved
An ever-increasing basic science literature supports the new survival.35,36 However, others have shown in large animal
paradigm that cellular injury is influenced not only by shock, but models that prolonged duration (8 h) of hypotension increases
also by our resuscitation strategies. Today, with the easy availability metabolic stress, tissue hypoxia, and mortality37,38 Still the
of advanced cellular research techniques, we can study the effect of majority of the pre-clinical data favors MAPs between 40 and
resuscitation fluids on the biological systems in much greater 60 mmHg or systolic blood pressure (SBP) between 80 and
detail. Review of the literature suggests that commonly used 90 mmHg. Furthermore, in each of these studies, hypotensive
resuscitation fluids (especially racemic lactated Ringer’s solution) resuscitation with crystalloids was beneficial compared to non-
can exaggerate the post trauma immune activation.23 Therefore, in resuscitated controls. An alternative means of hypotensive
addition to the immediate side effects (worsening of hemorrhage), resuscitation, particularly useful in pre-hospital or austere
delayed complications of fluid resuscitation such as systemic environments where accurate blood pressure measurement
inflammatory response, fluid overload (leading to compartment may not be feasible, is by fluid infusion at a pre-determined rate
syndromes, pulmonary edema etc), anemia, thrombocytopenia, (carefully selected to avoid over resuscitation). In animal
electrolyte/acid-base abnormalities, and cardiac and pulmonary studies, empiric rates of infusion have shown promise. Slow
complications must also be kept in mind.24 Excessive fluid resus- infusion rates with crystalloid have been shown to reduce
citation increases the chances of developing abdominal compart- organ injury,39 cause faster recovery of hemorrhage sup-
ment syndrome in critically ill surgical/trauma, burn, and medical pressed cell mediated immune function40,41 and reduce
patients.25e27 Similarly, in a multicenter study of burn patients, mortality. Overall, the data suggest that hypotensive resusci-
administration of excessive fluids (in excess of 25% of predicted) tation at a fixed rate of 60e80 cc/kg/hour generally maintains
increased the odds of ARDS (OR 1.7), pneumonia (OR 5.7), multiple controlled hypotension to a SBP of 80e90 mmHg (MAP of
organ failure (OR 1.6), blood stream infections (OR 2.9), and death 40e60 mmHg) and that this empiric control of infusion rates is
(OR 5.3).28 beneficial in hemorrhagic shock. Regardless of which approach
is selected (goal directed vs. fixed volume), these pre-clinical
1.2. New development data combined with the clinical evidence15,16 argues strongly
against routine large volume crystalloid resuscitation. The best
It is now being appreciated that resuscitation fluids, like other approach for urban trauma services (short transport times)
drugs, have indication for appropriate use, safe therapeutic doses, appears to be “scoop and run”, where unnecessary field inter-
potential side effects and complications. Despite a paucity of good ventions are avoided and the focus is on fast and efficient
randomized controlled trials (RCT) in this arena, clinical practices transport of the patient to the hospital.42
are rapidly changing. In general, large volume aggressive fluid ii. Hypertonic saline: Another new development is the renewed
resuscitation is becoming increasingly rare, and low volume, interest in hypertonic saline (HTS), not just as a volume
carefully guided resuscitation is more common. A few of these expander but also as an immune modulator. The use of HTS for
issues are discussed in more detail below: resuscitation from hemorrhage was first described in 1980,
when Velesco et. al,43 and DeFelippe et. al,44 reported in
i. Controlled hypotensive resuscitation: In appropriate patients separate studies that hypersomotic sodium chloride rapidly
(e.g. in young victims of penetrating trauma) limiting the rate expands plasma volume after major blood loss. Because of its
and volume of fluid resuscitation prior to hemorrhage control is ability to mobilize interstitial fluids into the vascular space,
rapidly becoming routine practice in large trauma centers. 250 ml of 7.5% saline can achieve results comparable to resus-
Blunt trauma patients with associated head injury are still citation with 2e3 L of 0.9% saline. Since the original reports,
resuscitated to a higher blood pressure, in an attempt to HTS or hypertonic saline combined with dextran (HSD) have
maintain adequate cerebral perfusion, but early use of blood been tested in a number of RCTs, without showing a clear
H.B. Alam / International Journal of Surgery 9 (2011) 5e12 7

survival advantage.45 A meta-analysis evaluated HSD as the conclusions have recently been questioned by a study that
initial treatment for hypovolemic shock by reviewing the suggests that the observed survival differences between
original records from six trials (and 604 subjects).46 Overall patients receiving high and low ratios in the first 24 h may
discharge survival rates were better with HSD resuscitation as simply be due to the fact that survivors live long enough to
compared to conventional resuscitation. HSD resuscitation was receive component therapy (survivor bias).66 Based on the
particularly effective for the sub-group of patients that had battlefield experience, the US Army has instituted a policy of
sustained head injury with a discharge survival rate of 38%, as using a 1:1:1 ratio of PRBC:FFP:platelets in the battlefield for
compared to a rate of 27% for the control group receiving saline. those that meet the criteria for massive resuscitation (expec-
All of these trials had used HTS as a volume expander, but ted to receive >10 units PRBC). However, no well-designed
a more advantageous effect of HTS administration may be the randomized clinical trial has conclusively identified the
attenuation of immune mediated cellular injury. A number of optimal ratios of blood components. Our own institutional
pre-clinical studies have demonstrated that HTS has the policy is to start FFP infusion as early as possible in massively
potential to modulate the immune response, with an overall bleeding patients, by activating Massive Transfusion Protocols
attenuation of immune mediated cellular injury.47e56 A small (MTP) which deliver PRBC:FFP in a ratio of 2:1, and administers
RCT has also shown that initial treatment of trauma patients 6 units of platelets for 10 units PRBC. Despite an ongoing
with HSD inhibits neutrophil adhesion molecule expression debate about the precise ratios, there is general agreement
and favorably modulates the inflammatory response.57 The that the blood products should be administered in the form of
recently established Resuscitation Outcome Consortium an MTP to optimize the processes of care and to improve
(ROC),58 funded by the National Institutes of Health and the US outcomes. The often disorganized process of blood component
Department of Defense initiated two multicenter trials of transfusion in the face of massive hemorrhage benefits from an
hypertonic resuscitation in blunt or penetrating trauma organized and standardized approach that delivers the needed
patients in hypovolemic shock, and severe traumatic brain blood products while avoiding their misuse. Despite these
injury. Both studies were designed to have three randomized obvious attractive features, in a recent review Malone found
groups comparing hypertonic saline/dextran (7.5% saline/6% only 10 such protocols published worldwide.67 The utility of
dextran 70, HSD), hypertonic saline alone (7.5% saline, HTS), MTP (using different ratios of blood components) has already
and normal saline (NS) as the initial resuscitation fluid for the been verified in some case controlled studies. Cotton tested
pre-hospital setting. In addition to the primary endpoints, the effectiveness of a Trauma Exsanguination Protocol (1:2:4
comprehensive data about the immunologic consequences of ratio of platelets:FFP:PRBC) by comparing patients treated
hypertonic resuscitation would also be collected. Unfortu- with the protocol (n ¼ 94 over 18 months) to a cohort of similar
nately, the interim analysis of the data was not favorable, HTD patients admitted during the prior 18 months (n ¼ 117). The
treated patients experienced higher early mortality and no study found that implementation of the protocol reduced 30-
overall benefit compared to the control arm (the full analysis day mortality (51% vs. 66%, p < 0.03), decreased intraoperative
remain unpublished at the time of this writing).59 Despite the crystalloid administration (4.9 L vs. 6.7 L, p ¼ 0.002), and
much lauded laboratory effects of hypertonic saline, this fluid reduced post-operative blood product use (2.8 units PRBCs vs.
has not been the magic bullet hoped for by many researchers. 8.7 units, p < 0.001; 1.7 units FFP vs. 7.9 units, p < 0.001; 0.9
Based upon these clinical data, HTS cannot be recommended units platelets vs. 5.7 units, p < 0.001).68 Dente conducted
for resuscitating trauma patients outside an approved trial. a similar study of an MTP (1:1:1 ratio of platelets:FFP:PRBC), by
Another fluid that remains controversial is albumin. A recent comparing matched patients during one year period before
report [post hoc analysis of patients from the Saline versus and after implementation of protocol (73 protocol, and 84
Albumin Fluid Evaluation (SAFE) study] suggests that albumin matched controls). Implementation of the protocol was found
should be avoided in patients with traumatic brain injury, as it to reduce mortality in the first 24 h (17% with MTP vs. 36% pre-
was associated with a significant increase in mortality.60 MTP, p ¼ 0.008), and at 30 days (34% vs. 55%, p ¼ 0.04), with
iii. Damage control resuscitation: An idea that is gaining a more pronounced impact in the blunt trauma patients.69 This
momentum due to the ongoing war (Iraq and Afghanistan) is study also showed that MTP patients required fewer overall
the concept of hemostatic/damage control resuscitation.61 transfusions of PRBCs and FFP after the first 24 h (2.7 units
Trauma patients are often coagulopathic due to shock and PRBCS vs. 9.3 units, p < 0.0001; 3 units FFP vs. 7.5 units,
tissue injury, and this coagulopathy can be worsened by p < 0.05). While further prospective research is needed to
resuscitation with crystalloids and packed red blood cells specify the exact ratios, there is convincing evidence that
(PRBC), as both are deficient in clotting factors. Observational implementation of standardized protocols for blood compo-
data from civilian trauma centers and the battlefield seem to nent transfusion improves processes of care, reduces overall
suggest that early administration of component therapy con- use of blood components, and improves outcomes.
taining fresh frozen plasma (FFP) and platelets may be bene- iv. Red blood cell substitutes: Although advances in viral
ficial.62,63 A recent retrospective analysis of mixed trauma screening have markedly decreased the risks of infectious
patients requiring surgery and massive transfusion compared transmissions, blood transfusion continues to be associated
FFP:PRBC ratios of 1:1 and 1:4, and showed that only 26% of with numerous serious side effects. In trauma patients, trans-
patients treated with the former ratio died while 87.5% of fusion of red blood cells (especially after prolonged storage) has
patients treated with the latter ratio died (p < 0.0001). In this been shown to disturb the immune system with an early
high risk group with an overall mortality of 55.5%, a 1:4 ratio of immune activation resulting in Systemic Inflammatory
FFP:PRBC increased the relative risk of dying by 18.9 Response Syndrome (SIRS), and a delayed immune suppression
(p < 0.001) when controlling for all other patient variables.64 which predisposes the patients to infections.70 As a matter of
Holcomb’s study of trauma patients at 16 trauma centers fact, transfusion of PRBC remains an independent risk factor for
who required massive transfusion found that an FFP:PRBC increased infections, multiple organ failure, length of hospital
ratio of 1:2 or higher (n ¼ 252) compared to lower ratios stay, and mortality.71e74 This has prompted many researchers
(n ¼ 214) was associated with improved 30-day survival (59.6% to focus their attention on testing alternative oxygen carrying
with high ratio vs. 40.4% with low ratio, p < 0.01).65 These solutions.75 A detailed discussion about the history and the
8 H.B. Alam / International Journal of Surgery 9 (2011) 5e12

development of these products is beyond the scope of this clearly sound, as has been validated by a number of subsequent
article. However, all of these solutions contain some form of studies.83e87 For optimal results, the resuscitation protocol must be
polymerized hemoglobin molecule and are thus labeled as initiated as soon as shock is diagnosed and should not be delayed
hemoglobin-based oxygen carriers (HBOC). A common until admission to the intensive care unit (ICU). Due to venous
problem with the HBOC relates to the scavenging of nitric oxide dilation, and increased capillary leak, most of these patients require
by the free hemoglobin molecule, which results in severe aggressive fluid resuscitation over the first 24 h. During this period,
vasoconstriction, a pro-inflammatory response, and end-organ in addition to ensuring adequate cardiac pre-load (e.g. central
injury. Different formulations differ in the mammalian source venous pressure, pulmonary artery occlusion pressure), parameters
of the hemoglobin and how it is cross-linked, as well as in of tissue perfusion and oxygen delivery (e.g. serum lactate, base
storage and length of shelf-life. Of the HBOCs tested thus far, deficit, urine output, central/mixed venous oxygen saturation,
only Hemopure or HBOC-201 (13 g/dL glutaraldehyde poly- cardiac output) should be carefully monitored. The SAFE study88 has
merized bovine hemoglobin) has remained in contention for shown that albumin and crystalloids are equally safe and effective
possible human use, while other formulations such as Poly- (except for patients with traumatic head injury). Surviving Sepsis
heme (10 g/dL glutaraldehyde polymerized human hemo- Campaign has recently reviewed the literature and published
globin) and HemAssist (10 g/dL diaspirin cross-linked human updated and comprehensive guidelines to guide the resuscitation in
hemoglobin) have fallen out of favor due to negative phase III adult and pediatric patients.89These guidelines also provide
clinical trials. In Sloan’s multicenter randomized clinical trial evidence-based recommendations regarding a wide spectrum of
(RCT) trauma patients in severe hemorrhagic shock received supportive/adjunctive therapies (e.g. glycemic control, steroids,
either 500 ml of saline (n ¼ 53) or HemAssist (n ¼ 58) within vasoactive agents, activated protein C etc).
60 min of presentation. The study found a higher 28-day
mortality in the treatment arm (47% for HemAssist vs. 25% for 2.2. Vasopressors and inotropes
saline, p ¼ 0.015).76 In another multicenter RCT, trauma
patients with severe hypovolemic shock were randomized to Within reasonable limits, blood flow through the tissue beds is
standard of care (n ¼ 62) or HemAssist (n ¼ 53) without any- more important than blood pressure. However, during septic shock
difference in 5- or 28-day mortality.77 Similar findings were autoregulation is not normal and perfusion can become linearly
reported with Polyheme in a subsequent RCT, where trauma dependent on blood pressure. Thus, after the initial fluid resusci-
patients in severe hemorrhagic shock were given either stan- tation (or concomitantly) hypotensive patients may require
dard of care (crystalloid and allogenic blood transfusion, administration of vasopressors to keep the mean arterial pressure
n ¼ 365) or up to 6 units of Polyheme (n ¼ 349). Even after >65 mmHg (which has been shown to preserve tissue perfu-
accounting for numerous protocol violations (17%), there was sion).90,91 Whenever possible, vasopressors should be started after
no mortality benefit in the treatment arm, and a higher rate of providing adequate initial fluid resuscitation. There is no compel-
adverse events (93% for Polyheme vs. 88% for controls, ling, high quality evidence that shows one agent to be superior to
p ¼ 0.041).78 A 2008 meta-analysis of 16 HBOC trials, including another.92 However, Surviving Sepsis Campaign recommends
four trials of trauma patients receiving HemAssist or Polyheme, “norepinephrine or dopamine as the first choice vasopressor agent
raised alarm as patients receiving HBOCs were noted to have to correct hypotension in septic shock (Grade IC)”.89 According to
a significant risk of myocardial infarction (RR, 2.71; 95% CI, them, norephephrine has some attractive features as it increases
1.67e4.40), and mortality (RR, 1.30; 95% CI, 1.05e1.61).79 This MAP (due to vasoconstriction), with little change in heart rate and
meta-analysis also included a single study data from a 2005 some increase in stroke volume. Dopamine is another good choice,
presentation to the U.S. Food and Drug Administration (FDA) on which increases MAP and stroke volume. However, it also increases
HBOC-201 use in surgical patients. HBOC-201 (Hemopure) has heart rate, which may not be desirable. Other choices have some
also been rested in a trauma patient population in South unattractive features. For example epinephrine can cause tachy-
African study but the final results of this trial remain unpub- cardia, decreased splanchnic circulation, and hyperlactemia.
lished.80 HOC 201 has been extensively tested with good results Phenylephrine is a pure vasopressor and is least likely to cause
in animal models (and is approved for veterinary use). It has tachycardia, but it decreases stroke volume. Vasopressin has
also been tested in a large phase III clinical trial (n-688) in recently gained popularity for treating refractory hypotension in
elective orthopedic surgical patients, where use of HBOC-201 septic shock patients, as there is a relative deficiency of this
resulted in less need for PRBC transfusion but a significant hormone in septic shock.93 However, a recent RCT-Vasopressin and
increase in serious adverse events.81 A phase II multicenter trial Septic Shock Trial (VASST), which enrolled 778 patients failed to
in trauma patients entitled Restore Effective Survival in Shock show a survival advantage of vasopressin (0.03 units/min) over
(RESUS) was first submitted to the FDA for approval in 2005. norepinephrine, or a reduction in overall rate of serious adverse
However, after an initial positive response the FDA has events.94 In addition to agents that restore the vascular tone,
repeatedly refused to allow the clinical trial to proceed due to patients with documented or suspected decrease in cardiac func-
concerns about patient safety, despite multiple revisions in the tion (elevated filling pressures and low cardiac output) should be
study protocol. Thus, based upon these current data, the use of given dobutamine as an inotropic agent.89 Administration of these
any HBOCs can’t be endorsed at this time outside of well- agents should be guided by serial measurements of markers of
designed, thoroughly vetted clinical trials. tissue oxygenation, filling pressures and cardiac output, without
making an attempt to achieve supra-normal levels.89
2. Septic shock
2.3. Blood products
2.1. Initial resuscitation
The optimal hemoglobin level has not been determined for
As opposed to hemorrhagic shock, early goal directed resuscita- severely septic patients. Rivers and associates in the early goal
tion has been shown to improve 28-day mortality in a single center, directed therapy trial82 used a target hematocrit of 30% in patients
prospective, RCT.82 Although the exact parameters used to guide who continued to show low central venous oxygen saturation. In
resuscitation in that study have been challenged, the basic concept is a more recent multi-institutional trail of mixed ICU patients (not
H.B. Alam / International Journal of Surgery 9 (2011) 5e12 9

necessarily septic shock patients) hemoglobin levels of 7e9 gm/dL resuscitation or blood transfusion, which makes this approach very
and 10e12 gm/dL were associated with identical outcomes.95 Thus, appealing for the logistically constrained pre-hospital and battlefield
it is reasonable to aim for target hemoglobin between 7 and 9 gm/ environments. It appears that HDAC inhibitors rapidly activate
dL if parameters of tissue oxygenation are adequate. But in cases of nuclear histones as well as numerous cellular proteins to create
depressed tissue oxygenation or in patients with other co-morbid a “pro-survival” phenotype in hemorrhagic and septic shock.105e109
issues (e.g. coronary artery disease, stroke, etc), hemoglobin levels Unpublished data also demonstrate that this approach is very
can be pushed up to 10e12 gm/dL to optimize the tissue oxygen promising for the treatment of traumatic brain injury. A number of
delivery. However, this area remains controversial and evidence- these HDAC inhibitors are currently being tested in phase I and II
based guidelines have been proposed by experts in the field to steer clinical trials (non-traumatic situations). We believe that additional
the transfusion practices in these critically ill patients.96 research in this arena could ultimately lead to a potent pharmaco-
logic adjunct to the treatment of hemorrhagic shock that works by
3. Future directions promoting cell survival during periods of lethal stress.

A number of new and exciting developments in the arena of 3.2. Emergency Preservation and Resuscitation (EPR)
resuscitation research have the potential of radically transforming
clinical care in the near future. Two such areas of research are Up to 80% of trauma deaths occur in the early post-traumatic
discussed here: phase,110 with exsanguination as the dominant etiology.2 Profound
shock from blood loss does not respond well to conventional
3.1. Pharmacologic therapy methods of resuscitation.14 Even when the underlying cause can be
treated and circulation restored, cerebral ischemia lasting 5 min or
Over the years, a number of pharmacologic agents have been longer invariably results in severe brain damage. Often the under-
tested as possible adjuncts to fluid resuscitation. These drugs cover lying injuries are reparable but the patient dies of irreversible shock
a wide spectrum including neuroendocrine agents, calcium channel or severe brain damage. In this setting, strategies to maintain cere-
blockers, ATP-pathway modifiers, prostaglandins, sex steroids, anti- bral and cardiac viability long enough to gain control of hemorrhage
oxidants, anti-inflammatory agents, and immune-modulators. and restore intra-vascular volume could be life saving. This requires
Although there is strong laboratory evidence of their beneficial an entirely new approach to the problem, with emphasis on rapid
effects on tissue perfusion, myocardial contractility, reticulo-endo- total body preservation, repair of injuries during metabolic arrest,
thelial function, cell survival, oxidative injury, and immune activa- and controlled resuscitation: Emergency Preservation and Resusci-
tion, majority of these agents are not yet in clinical use as tation (EPR). Currently, hypothermia is the most effective method for
resuscitative agents. A thorough discussion of the research in this preserving cellular viability during prolonged periods of ischemia.
area is beyond the scope of this article. However, a number of agents Although, no clinical studies have been conducted to test the ther-
aimed at correcting the circulatory and immunologic derangements apeutic benefits of hypothermia in trauma patients, numerous well-
of hemorrhage are worth mentioning as promising pharmacologic designed pre-clinical studies clearly support this concept. It should
adjuncts to resuscitation. Dr. Chaudry’s group has extensively studied be emphasized upfront that induced hypothermia and hypothermia
the role of sex steroids in cytokine responses and neutrophil adhe- secondary to shock are very different entities. Induced hypothermia
sion after hemorrhage; they have proposed estrogen and its analogs is therapeutic in nature whereas hypothermia, seen in severely
as possible beneficial treatments.97 Dr. Coimbra’s group has studied traumatized patients, is a sign of tissue ischemia and failure of
the phosphodiesterase inhibitor, pentoxyfylline, already widely used homeostatic mechanisms to maintain normal body temperature. It
for vascular disease due to its rheologic properties, as a treatment for is clear from the literature that rapid induction of deep/profound
hemorrhage because it reduces neutrophil activation and adhesion.98 hypothermia (<15  C) can improve otherwise dismal outcome after
A Cochrane review recently analyzed data on the opiate antagonist exsanguinating cardiac arrest.111e113 Depending on the degree of
Naloxone which has been studied based on the finding that central hypothermia, good outcomes have been achieved with cardiac
Mu, Epsilon, Kappa, and Delta receptors are activated during arrests of 15, 20, 30 and even 90 min in canine models.114,115
hemorrhagic shock and inhibit Caþþ channels; the data suggested Furthermore, the period of hypothermia can be safely extended to
that further clinical trials are needed to determine if the beneficial 180 min if blood is replaced with organ preservation fluids and low
effects on blood pressure by administration of Naloxone result in any flow cardiopulmonary bypass is continued (as opposed to no flow)
durable improvements in survival.99 A common thread across all of during the arrest period.116 Although ground breaking, the clinical
these potential agents is that they are already in wide clinical use for relevance of these original studies was somewhat limited by reliance
other disorders. Thus, there is great hope that with more clinical on pressure-controlled models of hemorrhagic shock (or no
evidence, these agents whose safety profile has already been tested hemorrhage), an absence of major injuries, and lack of surgical
for various non-trauma indications can be rapidly implemented as interventions. To fill these gaps, our team has utilized clinically
adjuncts to fluid resuscitation. Our group has been studying another realistic large animal models of lethal vascular injuries and soft
group of drugs, also already in wide clinical use for non-trauma tissue trauma to demonstrate that profound hypothermia can be
indications, in animal models of shock. Following hemorrhage, the induced through an emergency thoracotomy approach for total
stress of shock and resuscitation causes an immediate modulation of body protection, with excellent long-term survival and no neuro-
genes and proteins involved in a variety of cellular defense pathways logical damage or significant organ dysfunction.117 In a follow up
through an alteration in their acetylation status.100,101 We hypothe- study, it was established that lethal vascular injuries, above and
sized that histone deacetylase (HDAC) inhibitors such as valproic acid below the diaphragm, can be repaired under hypothermic arrest
(VPA) and suberoylanilide hydroxamic acid (SAHA) may have utility with >75% long-term survival.118 More importantly, it was shown
in the treatment of shock through restoration of normal cellular that hypothermia could be used successfully even after 60 min of
acetylation. We subsequently have shown that HDAC inhibitors normothermic shock (transport time), and that the surviving
rapidly reverse shock induced alterations, restore normal histone animals were not only neurologically intact but also had normal
acetylation, and improve survival in different models of otherwise cognitive functions. Subsequent studies have determined that to
fatal hemorrhagic shock and poly-trauma.102e104 Impressively, this achieve the best results, profound hypothermia must be induced
survival improvement was achieved without conventional fluid rapidly (2  C/min) and reversed at a slower rate (0.5 C/min).119,120
10 H.B. Alam / International Journal of Surgery 9 (2011) 5e12

Induction of hypothermia has been shown to preserve various cell the deleterious immunologic and cellular effects of hemorrhage and
types in the central nervous system, while providing some immu- resuscitation. This is an exciting area of future research but their use
nological advantages, and modulating cell survival pathways.121e123 remains to be validated in robust clinical trials. For now, early and
The optimal depth of hypothermia is 10  C, and decreasing the expeditious control of hemorrhage and modest, goal directed
temperature to ultra-profound levels (5  C) may actually worsen the resuscitation should be the standard of care.
outcome.124 If done appropriately, the safe duration of total body
preservation in poly-trauma is about 60 min,125 and it results in no Conflict of interest
increase in post-operative bleeding or septic complications.126 None.
Technically it is now feasible to induce hypothermia using small,
battery operated, portable equipment (suitable for austere settings Sources of funding
and pre-hospital environment).127 This is associated with excellent
“total body preservation” which may have significant implications National Institutes of Health and US Department of Defense.
not only for treatment of traumatic injuries but also for preserving
organs for transplant.128 Induction of hypothermia not only modu- Ethical approval
lates metabolism but also influences a vide variety of cellular and None.
sub-cellular mechanisms,129 including alteration in transcription of
numerous beneficial genes,130 the down-stream effects of which Acknowledgement
persists long after hypothermia. There is also some data from small
animal models to suggest that similar metabolic arrest (and tissue The author would like to acknowledge research support
preservation) can be achieved with other methods, such as inhaled provided by numerous grants by the Office of Naval Research, US
hydrogen sulfide.131 It may sound futuristic, but the expertise to Army Medical Research and Materiel Command, Defense Advanced
preserve the viability of key organs during repair of otherwise lethal Research Projects Agency, and National Institutes of Health.
injuries is now available,132 and a prospective multi-institutional
clinical trial is scheduled to start later this year.133

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